Square planar platinum complexes such as cis-dichlorodiammine platinum(II) [cis-(NH.sub.3).sub.2 Pt(II)Cl.sub.2 ] are known to be powerful anti-tumor agents (Rosenberg et al, J. Bacteriol, 93, 716-721, 1967) and (Rosenberg et al, Nature, 222:385-386, 1969). The drug has been shown to be clinically effective against carcinoma of the testis (Einhorn et al, Proc. Amer. Assn. Cancer Res, 19, 29 (1978)), head and neck (Caradonna et al, Proc. Amer. Assn. Cancer Res., 19, 95, (1978)) (abstract), ovary (Briscoe et al, Proc. Amer. Assn. Res., 19, 72 (1978)) (abstract), bladder (Troner et al, Proc. Amer. Assn. Cancer Res., 19, 161 (1978)) (abstract), and, to a lesser degree, against several other tumors (Gottlieb et al, Cancer Chemother. Rep., 59:621-628 (1975)), (Hill et al, Proc. Amer. Assn. Cancer Res., 13, 20 (1972))(abstract), Rossof et al, Cancer, 30:1451-1456, (1972)), and Talley et al, Cancer Chemother. Rep., 57:465-471(1973)). In combination with bleomycin and other drugs, increased activity has been demonstrated in cancers of the head and neck (Caradonna et al, supra), esophagus (Kelsen et al, Proc. Amer. Assn. Cancer Res., 19, 46 (1978))(abstract) and cervix (Slayton et al, Proc. Amer. Soc. Clin. Onc., 19, 335 (1978))(abstract). This combination has also been found to be curative in a high percentage of testicular cancers (Cvitkovic et al, 19. 296 (1978))(abstract). In combination with demethyl-epipodophyllotoxin ethylidene glucoside, a high degree of activity has been shown against oat-cell carcinoma of the lung (Sierocki et al, Proc. Amer. Soc. Clin. Onc., 19, 352 (1978)) (abstract). With desacetyl vinblastine amidsulfate there is increased activity with respect to epidermoid and adenocarcinomas of the lung (Gralla, R., Personal communication). In combination with cytoxan and adriamycin, activity has been reported in connection with carcinomas of the lung (Eagan et al, Proc. Amer. Assn. Cancer Res., 19, 78 (1978))(abstract), bladder (Troner et al, supra) and ovary (Briscoe et al, supra).
In mouse leumemias L1210 and P388, cis-dichlorodiammine platinum(II) is markedly potentiated by 2,2'-anhydro-.beta.-D-arabinofuranosyl-5-fluorocytosine (Burchenal et al, Cancer Res., 37:4098-4100 (1977)), demethyl-epipodophyllotoxin ethylidene glucoside, 6-diazo-5-oxonorleucine, methotrexate, and, to a lesser degree, by adriamycin (Burchenal et al, Biochimie, 60:961-965 (1978)).
Among the disadvantages associated with dichlorodiammine platinum(II) are the severe nausea and vomiting that it causes when administered to patients and the nephrotoxicity which severely limits the dose that can be given. In certain instances, high-tone hearing loss is also a problem. In addition, there is evidence that patients eventually develop resistance to cis-dichlorodiammine platinum(II).
In seeking solutions for these problems, various drugs, including nabilone, tetrahydrocannabinol, and metoclopramide have been used with varying degrees of success to control nausea and vomiting. Massive diuresis with intravenous infusion of mannitol has diminished the renal toxicity (Hayes et al, Proc. Amer. Assn. Cancer Res., 19, 169 (1978))(abstract) but has not completely solved the problem. Currently, the upper dosage limit appears to be approximately 120 mg/M.sup.2 in a single dose.
Dichloro-, malonato- and carboxyphthalato-1,2-diaminocyclohexane platinum(II) lack cross-resistance to dichlorodiammine platinum(II) and are highly effective both singly and in combinations against mouse leukemias (Burchenal et al, Biochimie, 60:961-965 (1978)). At the LD50 in mice, the malonato and carboxyphthalato derivatives cause much less renal toxicity than dichlorodiammine platinum(II) (Prestako et al, Cancer Treatm. Rep., (in press). Several of these derivatives, however, are poorly soluble in aqueous media. Larger doses of the malonato derivative are needed than with the more soluble dichlorodiammine platinum(II). Because of the poor solubility the amount of fluid necessary to solubilize this large amount of the malonato derivative necessary for treatment of the tumor is difficult to administer safely without causing cardiovascular problems.